TY - JOUR
T1 - Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1
AU - Cohen, Camille
AU - Le Goff, Océane
AU - Soysouvanh, Frédéric
AU - Vasseur, Florence
AU - Tanou, Marine
AU - Nguyen, Clément
AU - Amrouche, Lucile
AU - Le Guen, Julien
AU - Saltel-Fulero, Oriana
AU - Meunier, Tanguy
AU - Nguyen-Khoa, Thao
AU - Rabant, Marion
AU - Nochy, Dominique
AU - Legendre, Christophe
AU - Friedlander, Gérard
AU - Childs, Bennett G.
AU - Baker, Daren J.
AU - Knebelmann, Bertrand
AU - Anglicheau, Dany
AU - Milliat, Fabien
AU - Terzi, Fabiola
N1 - Funding Information:
We thank the LEAT, Histology and Imaging Platforms of Structure Federative de Recherche Necker, for technical assistance. We thank the LIOPA of Université de Paris for technical assistance in the bioluminescence protocol. We are grateful to Marco Pontoglio and Nicolas Kuperwasser for the critical reading of the manuscript. This work was supported by the Institut National de la Santé et de la Recherche Médicale, Université de Paris, Assistance Publique Hôpitaux de Paris, Agence Nationale Recherche.
Publisher Copyright:
© 2021 The Authors Published under the terms of the CC BY 4.0 license
PY - 2021/11/8
Y1 - 2021/11/8
N2 - The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for glomerular endothelial cells during aging. In fact, we discovered a detrimental cross-talk between senescent endothelial cells and podocytes, through PAI-1. In vivo, selective inactivation of PAI-1 in endothelial cells protected glomeruli from lesion development and podocyte loss in aged mice. In vitro, blocking PAI-1 in supernatants from senescent endothelial cells prevented podocyte apoptosis. Consistently, depletion of senescent cells prevented podocyte loss in old p16 INK-ATTAC transgenic mice. Importantly, these experimental findings are relevant to humans. We showed that glomerular PAI-1 expression was predictive of poor outcomes in transplanted kidneys from elderly donors. In addition, we observed that in elderly patients, urinary PAI-1 was associated with age-related chronic kidney disease. Altogether, these results uncover a novel mechanism of kidney disease and identify PAI-1 as a promising biomarker of kidney dysfunction in allografts from elderly donors.
AB - The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for glomerular endothelial cells during aging. In fact, we discovered a detrimental cross-talk between senescent endothelial cells and podocytes, through PAI-1. In vivo, selective inactivation of PAI-1 in endothelial cells protected glomeruli from lesion development and podocyte loss in aged mice. In vitro, blocking PAI-1 in supernatants from senescent endothelial cells prevented podocyte apoptosis. Consistently, depletion of senescent cells prevented podocyte loss in old p16 INK-ATTAC transgenic mice. Importantly, these experimental findings are relevant to humans. We showed that glomerular PAI-1 expression was predictive of poor outcomes in transplanted kidneys from elderly donors. In addition, we observed that in elderly patients, urinary PAI-1 was associated with age-related chronic kidney disease. Altogether, these results uncover a novel mechanism of kidney disease and identify PAI-1 as a promising biomarker of kidney dysfunction in allografts from elderly donors.
KW - PAI-1
KW - aging nephropathy
KW - endothelial–podocyte cross-talk
KW - kidney transplantation
KW - senescence
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U2 - 10.15252/emmm.202114146
DO - 10.15252/emmm.202114146
M3 - Article
C2 - 34725920
AN - SCOPUS:85118358563
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 11
M1 - e14146
ER -